tbuckley/cabot-search huggingface dataset:
Abstract 13872: CD70 Modulates Vascular Smooth Muscle Phenotype and Metabolism by Regulating Cellular Redox State
Authors: Arvind K Pandey, Markus Waldeck-Weiermair, Shambhu Yadav, William M Oldham, Thomas Michel, Joseph Loscalzo
Journal: Circulation (2023)

Introduction: The tumor necrosis factor superfamily (TNFSF) displays a wide array of vascular effects; however, the role of the TNFSF member CD70 is still being elucidated in the vasculature. We have recently described how CD70 modulates endothelial cell function and redox status by altering nitric oxide bioavailability and intracellular reactive oxygen species (ROS). However, the role of CD70 in vascular smooth muscle cells (VSMCs) is not known. We hypothesized that CD70 can alter VSMC phenotype and mitochondrial function through regulation of intracellular ROS. Methods: Human aortic VSMCs (AoVSMCs) were transfected with control or CD70-directed siRNA (n = 5-6). Cellular phenotype was assessed by scratch assay and collagen matrix gel contraction assay. Cell lysates were analyzed by Western blot and quantitative RT-PCR. Intracellular cytosolic hydrogen peroxide levels were measured using the fluorescent biosensor Hyper7 following stimulation by auranofin (50-70 cells per group averaged over 4 experiments). Metabolic profiling was performed with Seahorse assay, and mitochondrial membrane potential was assessed using TMRM dye (120 cells per group averaged over 3 experiments). Results: Following CD70 knockdown, AoVSMCs demonstrated augmented wound closure and decreased collagen matrix contraction. Expression of synthetic/proliferative markers, including vimentin, alpha-1 type I collagen, osteopontin, caldesmon-1, and c-Myc, was increased by up to 50%, and contractile markers including smoothelin, synemin, and synaptopodin-2 were decreased by up to 50%. Cytosolic hydrogen peroxide production was increased, with expression of NADPH oxidase (NOX) 4 and gp91phox (the catalytic subunit of NOX2) both increased by over 2-fold. CD70 knockdown led to a pronounced alteration in VSMC metabolic profile, with significantly decreased oxygen consumption rate (25%), extracellular acidification rate (45%), and maximal respiratory capacity (46%), as well as a decrease in mitochondrial membrane potential (37%). Conclusions: CD70 exerts a novel regulatory effect on VSMC phenotype; loss of CD70 promotes transition to a synthetic phenotype characterized by increased ROS with consequent metabolic reprogramming and mitochondrial dysfunction.
Abstract 12503: Both Heart Failure With Reduced and Preserved Ejection Fraction Should Be Included in the CHA <sub>2</sub> DS <sub>2</sub> -VASc Score: A Taiwanese Longitudinal Cohort
Authors: Chien-Chien Cheng, Pang-Shuo Huang, Chia-Ti Tsai
Journal: Circulation (2023)

Background: Congestive heart failure (CHF) is a known risk factor for atrial fibrillation (AF)-related thromboembolic stroke. The CHA2DS2-VASc score incorporates CHF but was developed when it primarily referred to patients with reduced ejection fraction (HFrEF). CHF now includes preserved ejection fraction (HFpEF) patients. Therefore, the distinction between stroke risk of AF patients with HFpEF and HFrEF is important for improving risk assessment and management strategies for AF patients. Methods: In a longitudinal study utilizing the National Taiwan University Hospital Integrated Medical Database (iMED), 8358 patients with atrial fibrillation (AF) were followed from January 2010 to December 2020 (mean follow-up 3.76 years). Among these patients, 4654 (55.7%) had no history of CHF, 2374 (28.4%) had HFpEF, and 1330 (15.9%) had HFrEF. HFpEF was defined as patients with a left ventricular ejection fraction (LVEF) of 55% or higher. The study evaluated the risk of ischemic stroke using Cox models adjusted for all components of the CHA2DS2-VASc score. Results: Patients with HFpEF were older, more frequently female, and had a higher prevalence of previous stroke and hypertension. They also had a higher mean CHA2DS2-VASc score (4.08±1.502 vs. 3.83±1.571, p&lt;0.001) and a higher risk of stroke compared to HFrEF patients (30.1% vs 26.3%, p=0.014). After adjusting for other stroke risk factors with CHA2DS2-VASc score components, there was no significant difference in the risk of stroke between the HFpEF and HFrEF groups (p=0.799). Conclusion: Both HFpEF and HFrEF were associated with a higher risk of stroke. Thus, the criteria of "CHF" in the CHA2DS2-VASc score should include HFpEF as well.
Abstract 13838: Hemostatic Disorder During Left Ventricular Assist Device Implantation in Swine
Authors: Johanna Reuter, Florian Meissner, Martin Buechsel, Hendrik Straky, Michelle Costa Galbas, Martin Czerny, Wolfgang Bothe
Journal: Circulation (2023)

Introduction: Implantation of left ventricular assist devices (LVAD) conventionally requires the use of cardiopulmonary bypass (CPB). Among others, mechanical circulatory support devices favor intraoperative hemostatic disorder. Hypothesis: Despite the high risk of severe bleeding and thromboembolic complications, little is known about the intraoperative extent of hemostatic disorder during LVAD implantation.This study aimed to determine the extent of hemostatic disorder during LVAD implantation in a porcine model under CPB and LVAD support, separately. Methods: We performed LVAD implantation in 10 female German Landrace pigs (body weight 104 ± 13 kg). Blood samples were collected three times: at (1) Baseline, (2) after CPB and (3) after LVAD. For CPB, cannulation of the left jugular vein and right femoral artery was performed. After sternotomy and pericardiotomy, apical coring was performed under CPB. A continuous-flow LVAD with transventricular outflow graft was implanted. For CPB and LVAD, a flow rate of 3-7 L/min and a rotational speed of 4000 to 7200 rpm were aimed, respectively. Hemostatic laboratory markers from all times were compared by Wilcoxon signed rank test. Results: Compared to Baseline, CPB led to a significant decrease of fibrinogen and antithrombin as well as an increase of von Willebrand factor (vWF) ratio and D dimer (DD). Compared to after CPB, there was a continued decrease of antithrombin and an increase of DD, as well as a significant increase of vWF and vWF activity under LVAD support. Conclusion: Among others, CPB and LVAD separately contribute to hemostatic disorder during LVAD implantation. Human laboratory markers allowed early detection of intraoperative hemostatic changes in pigs. Further studies are needed to investigate whether off-pump LVAD implantation reduces perioperative hemostatic disorder.
Abstract 15604: Dietary Patterns, Blood Pressure and Proteinuria in a West African Chronic Kidney Disease Population
Authors: Edward P Kwakyi, Runqi Zhao, Ifeoma Ulasi, Rulan Parekh, Fatiu Arogundade, Dwomoa Adu, Adaobi Solarin, Yemi Raji, manmak mamven, Diane Mitchell, Sushrut Waikar, Akinlolu O Ojo, RASHEED GBADEGESIN, Ernestina Eduful, Titilayo Ilori
Journal: Circulation (2023)

Introduction: There is little known about the impact of dietary patterns on blood pressure (BP) in West Africa. Our study describes associations of dietary patterns with BP and albuminuria and is the first study to do so in a well-phenotyped West African CKD cohort. Research question: What are the associations of dietary patterns with BP and proteinuria in West African CKD patients? Methods: We performed a cross-sectional analysis of participants from the Diet, Apolipoprotein L1, and CKD study; an ancillary study under the H3 Africa Network. We analyzed 24-hour dietary recalls in 583 participants. Dietary patterns were derived via principal component analysis, and the first 3 principal components with eigenvalues &gt; 1 were selected. We measured proteinuria using 24-hour urine samples. Mixed effect linear regression models were used to estimate the β coefficient and 95% confidence interval for the quartiles of the dietary patterns with BP and proteinuria after adjusting for covariates. Results: The mean age was 49±17 years with 51% males and the mean eGFR (2009 CKD-Epidemiology collaboration formula) was 68±39 mL/min/1.73m 2 . The median 24-hour urine protein was 0.31g (IQR=0.13-1.07). We identified the Dried fish, Oils and vegetables; Poultry and Cereal; and the Fruit and Cereal dietary patterns . Compared to Q1 (lowest consumption), higher quartiles of intake of the Poultry and Cereal dietary pattern were associated with lower systolic BP (SBP) and diastolic (DBP). Higher consumption of the Poultry and Cereal dietary pattern was associated with lower 24hr urine protein, with a significant p for trend (p=0.05). Compared to Q1, Q4 of this pattern was associated with reduced odds of proteinuria ( Table 1 ). Conclusions: Consuming a Poultry and Cereal dietary pattern may be beneficial for BP and proteinuria in West African CKD patients.
Abstract 16917: Ross Procedure versus Biological Aortic Valve Replacement in Adults in a Single Center Setting: A Propensity Score Matched Comparison
Authors: Kiril Penov, Tobias Merz, Dejan Radakovic, Nodir Madrahimov, Khaled Hamouda, Armin Gorski, Rainer Leyh, Constanze Bening
Journal: Circulation (2023)

Background: Guidelines suggested alternative for middle-aged adults undergoing aortic valve replacement is mechanical prosthesis, followed by the Ross procedure (Ross). However, increasingly more patients receive a biological prosthesis (bio AVR) even in young adult age. Is this practice justified? Objectives: To compare long-term outcomes in a single center after Ross vs bio AVR. Methods: For this retrospective study, we screened 2624 patients 04/2007 - 03/2020. Out of these, 231 received Ross, and 2393 received bio AVR ± CABG or aortic surgery. Exclusion criteria: emergency surgery and concomitant mitral or tricuspid valve surgery. Using 1:1 propensity score 99 matches were paired. Primary end-point was all-cause mortality. Secondary end-point was composite of death, need for repeat intervention, and stroke (MACCE). Median follow-up was 7.5 years (IQR: 4.4 - 10.6 years). Results: Mean age for Ross was 56.2±6.1, and for bio AVR was 56.2±5.9. Actuarial 10-year survival for Ross was 89.3%, but significantly lower for the bio AVR 57.9%. All-cause mortality was significantly lower after the Ross procedure compared to the bio AVR (log rank p&lt;0.001). The MACCE-free survival was significantly better after the Ross procedure (log rank p&lt;0.001). Conclusion: In middle-aged adults undergoing AVR, the Ross procedure was superior over the conventional bio AVR after 10 years F/U. Bio AVR should therefore be avoided in this patient population every time possible. Overall long-term survival after Ross vs bio AVR: MACCE free survival after Ross vs bio AVR:
Abstract 13817: Very Short-Term Blood Pressure Variability by Pulse Transit Time-Based Measurements During Sleep Predicts Future Cardiovascular Events in Patients With Ischemic Heart Disease
Authors: Ryo Ogawara, Tomofumi Misaka, Shohei Ichimura, Yusuke Tomita, Tetsuya Tani, Yu Sato, Shunsuke Miura, Tetsuro Yokokawa, Akihiko Sato, Takeshi Shimizu, Takamasa Sato, Masayoshi Oikawa, Atsushi Kobayashi, Akiomi Yoshihisa, Yasuchika Takeishi
Journal: Circulation (2023)

Background: Blood pressure (BP) variability (BPV) is recognized as an independent factor associated with cardiovascular (CV) events. However, monitoring very short-term BPV, which occurs within seconds or minutes remains challenging, and its prognostic impact has yet to be established. In a previous study, we reported that pulse transit time (PTT) enabled monitoring beat-to-beat BP, which is useful for evaluating very short-term BPV during sleep. Aims: This study aimed to clarify the prognostic relevance of PTT-based very short-term BPV during sleep. Methods and Results: We conducted a prospective study involving 206 consecutive hospitalized patients (mean 67.6 years old, 78.1% male) with ischemic heart disease. PTT-driven BP was continuously recorded during the night. To assess very short-term BPV, we defined the PTT index as the average number of acute transient rises in systolic BP (≥12 mmHg) within 30 s/h, and the standard deviation (SD) of PTT-BP was calculated. We followed up with patients for a median of 759 days and observed 49 CV events, including cardiac death, worsening heart failure, acute coronary syndrome, and ischemic stroke. Kaplan-Meier analysis revealed that patients with higher PTT index, as well as higher SD of mean and diastolic PTT-BP were associated with increased CV events ( Figure ). In a multivariate Cox proportional hazards analysis, after adjusting for confounding variables, PTT index, as well as SD of mean and diastolic PTT-BP were independently associated with increased risks of adverse events (hazard ratio, 1.019, 1.245, and 1.244; P = 0.02, 0.04, and 0.09, respectively). Conclusions: PTT-index and SD of mean and diastolic BP during the night, which represent measures of very short-term BPV, predicted the future risk of CV events in patients with ischemic heart disease through the PTT-driven approach and may serve as a target to reduce the residual risk in such patients.
Abstract 13835: Glutaminolysis Boosts Cardiac Performance Under High Workload via Enhancement of Mitochondrial GSH
Authors: Xinpei Wang, Mengya Feng, Xing Zhang, Jia Li, Feng Gao
Journal: Circulation (2023)

Introduction: Glutamine, the most abundant non-essential amino acids in circulation, serves as an important energy source in proliferating cells. Previous evidence has indicated that glutamine is not a primary carbon source for the tricarboxylic acid cycle in cardiomyocytes under physiological workload. However, current clinical studies reveal that impaired glutaminolysis is associated with heart failure and an increased risk of cardiovascular events. Hypothesis: We hypothesized that impaired glutaminolysis would compromise cardiac function, especially under conditions of increased workload. Methods: We analyzed cardiac structure and function in a mouse model with cardiac-specific knockdown of glutaminase (GLS), a key enzyme of glutaminolysis. Cardiac reserve was assessed by isoproterenol stress echocardiography. We performed transcriptomic, 13 C isotopic labeling, and reactive oxygen species emission analyses to investigate the underlying mechanism. Results: GLS deficiency impaired cardiac reserve and exercise capacity in mice, but had no discernible effects on cardiac structure or function under baseline condition. Inhibition of glutaminolysis in pressure-overloaded hearts further exacerbated cardiac dysfunction, indicating the critical role of glutaminolysis in cardiomyocytes under high workload. Mechanistically, glutaminolysis maintained cardiomyocyte function by balancing intracellular redox status through the production of glutathione (GSH), particularly in mitochondria. Inhibition of glutaminolysis decreased both cytosolic and mitochondrial GSH levels, resulting in compromised cell contraction in isolated cardiomyocytes under high workload. Additionally, heterologous expression of an engineered mitochondrial GSH biosynthetic enzyme increased mitochondrial GSH levels and enhanced cardiac reserve in GLS knockout mice. Conclusions: Our findings establish the previously unrecognized role of glutaminolysis in cardiomyocytes, maintaining cardiac reserve via upregulating mitochondrial GSH levels. This suggests that targeting glutaminolysis is a potential strategy for improving cardiac reserve and managing cardiac diseases.
Abstract 16922: One-Year Latent Health Status Trajectories in Patients With Symptomatic Peripheral Artery Disease
Authors: Scott Grubman, Gaelle Romain, Jacob Cleman, Lindsey Scierka, Carmen Pajarillo, Jonathan Kluger, Carlos Mena-Hurtado, Kim G Smolderen
Journal: Circulation (2023)

Background: Symptomatic peripheral artery disease (PAD) can dramatically impact health status. We aimed to characterize typical health status trajectories following initiation of PAD specialty care and to identify demographic, medical, and psychosocial predictors of suboptimal recovery. Methods: Adults with new or worsening PAD (Rutherford 1-3) presenting to vascular clinics in the US, Australia, and Netherlands 2011-2015 in the PORTRAIT study were included. Demographics, comorbidities, and psychosocial measures including the EQ-5D (generic health status), PHQ-8 (depression), GAD-2 (anxiety), PSS (stress), ESSI (social support) were obtained upon initial evaluation. Peripheral Artery Questionnaires (PAQ; 0-100, higher = better PAD-specific health status) were administered at 0, 3, 6, and 12 months. Latent trajectory modeling was used to identify typical PAQ score trajectories by Bayesian information criterion. Predictors of favorable vs. poor recovery trajectory (&lt;10-point PAQ increase at 1 year) were assessed by logistic regression. Missingness was handled by multiple imputation. Results: The final cohort included 1,204 patients, had a mean age of 67.5 (±9.4) years, was 62.5% male, and 82.1% white. A 5-group model best fit the data (Figure). At 1 year, the High (n=401), Intermediate (n=400), and Sustained Response (n=98) groups demonstrated “favorable” mean PAQ changes of +16.8 , +24.0, and +59.4 points, respectively. The Low (n=150) and Transient Response (n=155) groups demonstrated “poor” recovery of +8.6 and +7.6 points, respectively. Significant predictors of poor recovery included age, nonwhite race, worse EQ-5D, and worse PHQ-8 (all p&lt;0.05). Conclusion: Patients with symptomatic PAD follow predictable health status trajectories after initiating care. Poor recovery trajectory is predicted by age, nonwhite race, worse generic health status, and depressive symptom burden. Further emphasis should be placed on these factors during treatment.
Abstract 19112: Hemodynamic Optimization of Left Ventricular Assist Devices During Right Heart Catheterization Ramp Studies
Authors: Alexander Hajduczok, Carly Maucione, Laura DiChiacchio, Brinnae Bent, John Boehmer
Journal: Circulation (2023)

Background: Studies have shown that hemodynamic LVAD ramp studies can be used to optimize speeds and improve clinical outcomes, yet these studies lack external validation. Methods: 470 LVAD patients, including 3 LVAD subtypes, were retrospectively analyzed and 53 ramp studies were identified. Measurements (RA, mean PA, PCWP, and CI) were taken at speeds +/- 20% of the manufacturer recommended set speed for HM2, HM3, and HVAD devices. Primary outcomes were all-cause and heart failure (HF) hospitalizations in the 6-month period pre- and post-ramp study. Secondary outcomes included final LVAD speed and hemodynamic measurements following ramp study. Time to first hospitalization and cumulative incidence rate of all-cause and HF hospitalization were reported. Results: Baseline characteristics of 53 studies included: mean age of 60.1 (+/- 10.9), 84.9% male, 56.6% ischemic etiology, 71.7% destination therapy, and average NYHA class and INTERMACS of 2.5 (+/- 0.7) and 5.9 (+/- 1), respectively. 38 of 53 studies (71.7%) showed PCWP decompression &gt;20%, with average PCWP decompression of 51.2% (+/- 21.0%), and CI increase of 22.5% (+/- 18.7%). Optimal LVAD speeds were chosen to maintain CI &gt; 2.2, PCWP &lt; 15 and minimize RAP, in the absence of suction events. 31 (58.5%) of studies resulted in an LVAD speed change and 16 (30.2%) of studies resulted in diuretic change. All-cause and HF hospitalizations were significantly decreased in the 6-months following ramp studies compared the 6-months pre-ramp (total days hospitalized for all causes: 12.0 vs 26.6, p=0.002; total days hospitalized for HF, 4.8 vs 22.1, p=0.0003). Speed changes were associated with a nonsignificant improvement in time to first hospitalization. Conclusion: This externally validates previous data suggesting that LVAD hemodynamic ramp studies decrease hospitalizations. Larger studies and longer follow up may elucidate specific hemodynamic targets to improve mortality and further reduce rehospitalizations.
Abstract 12532: Maximal Exercise Capacity is Inversely Related to Incident Peripheral Artery Disease: Data From the Henry Ford Exercise Testing (FIT) Project
Authors: Jonathan K Ehrman, Steven J Keteyian, Herbert D Aronow, Syed Ahsan, Michael J Blaha, Mouaz H Al-Mallah, Clinton A Brawner
Journal: Circulation (2023)

Introduction: Maximal exercise capacity (EC) is a strong, independent predictor of incident coronary and cerebrovascular disease. However, less is known about the relationship between EC and incident peripheral artery disease (PAD). Using data from the Henry Ford Exercise Testing (FIT) Project, we evaluated the relationship between EC and incident PAD. Hypothesis: EC, measured in metabolic equivalents of task (METs), is inversely related to incident PAD. Methods: We assessed 41,268 patients (age= 55±12 yrs, 49% female, and 64% white) who completed a clinically indicated exercise stress test between January 1991 and June 2009 at a Henry Ford Health facility. Patients with established PAD at the time of testing were excluded. METs were estimated from peak treadmill speed and grade and standardized to the equivalent of a 50-year-old male to account for differences in absolute risk for a given MET level by age and sex. METs were categorized as &lt;6, 6-9, 10-11, and &gt; 12. ICD9 codes 440.XX and 443.9 were used to identify first incidence of PAD from the test date through June 2010. Multivariable Cox regression was used to relate METs to incident PAD. Patients were censored at the date of death or last clinic visit. Results: During a median follow-up of 7.1 years (IQR 4.2-11.1 yrs) there were 2,596 (6%) incident diagnoses of PAD. In the adjusted analysis, each 1 MET increase in maximal EC was associated with a 7% lower risk of PAD (aHR=0.93 [0.91, 0.94]). There was a graded, inverse risk of incident PAD by MET category (see Table). A significant interaction was noted for race (overall p=.04; white [HR=0.93 (0.92, 0.95)] vs black [HR=0.91 (0.88, 0.93)], p=.02; white vs other [HR=0.97 (0.87, 1.07)], p=0.47), but not for sex (p=.79). Conclusion: In a diverse cohort that completed a clinically indicated exercise stress test, higher EC measured in METs, is independently and inversely associated with a lower risk of incident PAD.